Fig. 9. Overview of naturally occurring anti-CRISPR responses.

CRISPR/Cas adaptive immunity consists of three distinct stages: foreign DNA acquisition, crRNA transcription/maturation, and interference (target recognition and cleavage). However, strong selective pressures exerted by CRISPR-Cas has led to the emergence of increasingly powerful anti-CRISPR defenses to combat its cleavage. We discovered that various ISs insert into the cas gene, thereby engaging in the host’s fitness trade-off (balance) between positive and negative aspects of CRISPR-Cas interference. Also, many bacteriophages have evolved anti-CRISPR (Acr) proteins or site-specific integrases that can disrupt CRISPR-Cas mechanisms, and some single-nucleotide polymorphisms (SNP) and indel mutations in cas genes, spacers, or genomic targets can deactivate CRISPR-Cas. Overall, under certain stress conditions, the CRISPR-Cas system may undergo compensatory mutations which can mediate the fitness trade-off between the uptake of beneficial genes and defense against infection.